Early cancer detection is not only critical in providing curative therapies for the vast majority of solid malignancies and preventing mortality, but also reducing morbidity and costs. However, most existing strategies for early detection suffer from poor specificity: they are as likely to cause complications and deaths from false positives or overdiagnosis of non-invasive cancers as they are from identifying true cancers at an early stage. Recent data from our own group and others show that Circulating Tumor Cells (CTCs) may be shed in significant numbers into the blood stream of patients with invasive but localized and early-stage cancers. These observations suggest that, rather than being a rare and late event in the evolution of cancer, the presence of CTCs may be an early herald of tumor vascular invasion, preceding a considerable period of time for the eventual establishment of viable distant metastases. Our specific strategy is to develop a highly sensitive digital readout based on RNA in CTCs using the microfluidic CTC isolation approach (CTC-iChip) combined with digital droplet RNA (ddPCR) measurement platform. It is important to note that the CTC-iChip is unique in that it makes no a priori assumption about the type of the tumor cells and as such it applies to all cancers. Detecting tumor lineage specific RNA within noninvasively accessed tumor cells is the technology most likely to be not only highly specific and sensitive but also universal for early detection of invasive cancer. To this end, we have 3 distinct but interrelated Aims. In Aim I, we will integrate CTC-iChip and digital droplet PCR to develop a highly specific and sensitive RNA-iChip. In Aim II, we will select two cancers for which sensitive but nonspecific screening tests are currently available, prostate and lung cancer, and we propose to transform these into robust and reliable tests using RNA-iChip that would enable broad screening for invasive and curable cancers. In Aim III, we propose to develop the point of care RNA-iChip broad dissemination beyond academic medical centers to local hospitals, oncology clinics and to physicians' offices. Success with prostate and lung cancers would have a profound impact in decreasing cancer morbidity and mortality, and open a path toward broad-based early detection of multiple cancers.